15,16 beta-methylene steroids of the estrane and androstane series and methods for preparing same



United States Patent 3,470,160 15,16 BETA-METHYLENE STEROIDS OF THEESTRANE AND ANDROSTANE SERIES AND METHODS FOR PREPARING SAME OtfriedSchmidt, Klaus Prezewowsky, and Rudolf Wiechert, Berlin, Germany,assignors to Schering A.G., Berlin, Germany No Drawing. Filed Mar. 28,1967, Ser. No. 626,426 Claims priority, application Germany, Apr. 2,1966,

ch 38,777 Int. Cl. C07c 169/10, 169/22; A61k 17/00 U.S. Cl. 260-23955 7Claims ABSTRACT OF THE DISCLOSURE 15,16,3-methylene steroids and theirpreparation.

The invention relates to methods of preparing 15,16,8-methylene-steroids, preferably steroids of the estrane and androstaneseries, having in part the formula characterized in that corresponding A-17-ketosteroids are methylenated at the 15,16 double bond.

In carrying out the methylenation, one starts from atrirnethyloxosulfonium salt (such as the halide, perchlorate, methylsulfate) which is reacted in dimethylsulfoxide with a base, such aspotassium or sodium tert-butylate or sodium hydroxide in a solvent suchas dimethylsulfoxide or dimethylformamide to formdimethylmethylenesulfonium oxide and the latter, without being isolated,is reacted, with the a,/3-unsaturated ketone at a temperature between 40and 100 C., preferably at room temperature.

Some facts about the reaction of a,fiunsaturated ketones withdimethylmethylenesulfonium oxide have become known (see Chem. Ber. 98(1965) 1470, and German Patent 1,183,500). Still the smooth course ofthe reaction in the instant case is surprising because those skilled inthe art know that A -17-ketones are readily deconjugated to A -17ketones in the presence of an alkaline catalyst, or converted to A-17-ketones of the 145 series (JACS 82 (1960) 3209). Moreover, theaddition according to the invention at the 15,16-double bond in,Bposition is surprising because it is known that the methylene group isintroduced in a-position when dimethylmethylenesulfonium oxide is used(German Patent 1,183,500). 7

Methylenation may also be achieved by adding diazomethane to the A-double bond, and by subsequently splitting the pyrazoline ring soformed by known methods. It is also surprising in the diazomethanemethod that the methylene group is added to the 15,16-double bond in thefi-position because it is known from the literature that the methylenegroup when added by this method is also added in the a-position (cf.German Patent 1,107,663).

Other than the A -17 ketone, the starting material may contain any othergroups which are inert to the methylenation agent. Inert groups, for thepurpose of this discussion, include for example, hydroxyl groups whichmay also be present in the esterified or etherified condition, alsoalkyl radicals and halogen atoms. It must be considered, however, thatparticularly reactive halogen atoms may participate in the reactionunder the conditions of methylenation. Thus, chlorohydrines andbromohydrines are converted to epoxides in an alkaline medium. Also, a

3,470,160 Patented Sept. 30, 1969 halogen ion may be exchanged againstan added anion. However, the methylene addition reaction proper at the A-double bond is not impaired by such secondary reactions.

Among interfering groups, mention may be made of readily reactingsaturated keto groups, for example, in position 3, or nap-unsaturatedketo groups which still carry a hydrogen atom at the carbon atom in13-p0siti0n, such as A -3-ketones.

Preferred starting materials of the method of the invention are A-17-ketosteroids having the following configurations in the A-ringwherein R is alkyl, preferably lower alkyl, or acyl,

wherein Z is hydrogen or methyl.

The 15,16,3-methylenesteroids which may be prepared according to theinvention may be used in the field of medicine because of their valuablepharmacological properties, or they may serve as novel startingmaterials for preparing new steroids because of their reactivestructure.

15,16fi-methylene-estrone-methyl ether, for example, may be converted to15,MIR-methylene-19-nor-testosterones which proved to be high effectiveprotein-anabolic and relatively weak androgenic agents.

The following examples are illustrative but not restrictive of thepreparation of compounds according to the invention.

Example 1 ml. dimethylsulfoxide, 1.44 g. sodium hydride (2.88 g. of a50% suspension in oil, 60 millimol), and 13.25 g. trirnethyloxosulfoniumiodide ('60 millimol) are stirred at room temperature until thedevelopment of hydrogen ceases (approx. 40 minutes). Then 14.42 g. A-5a-androstene-3 3-ol-17-one (50 millimols) are added and the mixture isstirred at room temperature for three additional hours. Precipitationwith ice water yields 14.4 g. of a crude product. It is filtered inbenzene over the 20-fold amount of silica gel, and the residue obtainedafter evaporation of the eluate is recrystallized from diisopropylether/acetone. There are obtained 10.5 g. 15,16,8-methyIene-Sa-androstane-3j3-ol-17-one of melting point 231233 C.

Example 2 220 ml. dimethylsulfoxide, 2 g. sodium hydride, and 18 g.trimethyloxosulfonium iodide are stirred at room temperature until thedevelopment of hydrogen stops. 20 g. 15-dehydroestrone-methyl-ether arethen added and the mixture is stirred at room temperature for threeadditional hours. Upon precipitation with ice water, there are obtained20 g. of a crude product which is filtered in benzene over a 25-foldamount of silica gel. The fractions which are uniform according to theirthin layer chromatograms yield 14.16 g. 15,16,3-methylene-A-estratriene-3-ol-17-one-3-methyl ether of melting point 169- 170.5 C.(from diisopropyl ether).

Example 3 A solution of 2 g. A -estratetraene-3-ol-17one- 3-methyl etherin 15 ml. methylene chloride is added to 100 ml. of a solution ofdiazomethane in ether (prepared from g. nitrosomethylurea). The mixtureis left to stand at room tenperature for two days, the precipitatedpyrazoline derivative is filtered 01f and recrystallized from acetonemethylene chloride. There are obtained 1.39 g. of melting point 22 0-223C. (with gas development).

1 g. pyrazoline derivative is added to a mixture of 80 ml. acetone and0.3 ml. boron trifluoride etherate, and the resulting mixture is stirred30 minutes at room temperature. A crude product is precipitated by meansof ice water, and the dried crude product (0.91 g.) is crystallized fromdiisopropyl ether whereby 0.82 g. 15,16,8-methylene- A-estratriene-3-ol-17-one3-methyl ether of melting point 169170 C. isobtained.

Example 4 (a) Water is removed by azeotropic distillation from solutionsof 6.4 g. A -estratetraene3-o1-17-one in 200 ml. benzene and of 240 mg.p-toluenesulfonic acid in 20 ml. benzene. The solutions are cooled toroom temperature and combined, mixed with 40 ml. dihydropyrane, andstirred for 1.5 hours. The acid is ultimately neutralized by shakingwith cold, dilute sodium bicarbonate solution, and the sodiumbicarbonate is washed out with water until the washings are neutral.After drying and evaporation of the solvent there is obtained a residueof A -estratetraene-3-ol-17 one 3 tetrahydropyranyl ether, which, whenrecrystallized from ethyl acetate, melts at 180- 182 C. Yield: 6.74 g.

(b) A suspension of 2.29 g. trimethyloxosulfonium iodide in 50 ml.dimethylsulfoxide is mixed with 429 mg. sodium hydride suspended in oil(50% and the mixture is stirred under nitrogen at room temperature for45 minutes. Thereafter, 2.6 g. A -estratetraene-3-ol-17-one-3-tetrahydropyranyl ether are added, and the mixture obtained isstirred under nitrogen for hours at room temperature. The base issubsequently neutralized with glacial acetic acid, the batch is stirredinto ice water, and the precipitate is filtered off. When the residue isrecrystallized, there are obtained 1.8 g. of 15,16 3-methylene- A-estratrieneJ-ol-l7-one-3-tetrahydropyranyl ether of melting point166169 C.

Example 5 1 g. A -estratetraene-3-ol-17-one is reacted with a solutionof dimethylmethylenesulfonium oxide prepared from 1.16 g.trimethyloxosulfonium iodide, 220 mg. sodium hydride in 50% oilsuspension, and ml. dimethylsulfoxide by analogy with Example 1, and thereaction mixture is worked up. There is obtained 1 g. 15,165-methylene-A-estratriene-3-ol-17-one.

Example 6 900 mg. 41 -estratetraene-3-ol-17-one-3-acetate are reactedwith a solution of dimethylmethylenesulfonium oxide prepared by analogywith Example 1 from 1.04 g. trimethyloxosulfonium iodide, 200 mg. sodiumhydride in 50% oil suspension, and 25 ml. dirnethylsulfoxide, and thereaction mixture is worked up. The crude product is subsequentlyacetylated by means of acetic anhydride and pyridine. 600 mg.15,16fl-methylene- A -estratriene-3-ol-17-one-3-acetate are obtained.

4 Example 7 175 ml. dimethylsulfoxide, 144 g. sodium hydride (2.88 g. ofa 50% suspension in oil, 60 millimol), and 13.25 g.trimethyloxosulfonium iodide (60 millimol) are stirred at roomtemperature until gas development stops (about 40 minutes). Then, thereare added 16.5 g. A -5/3-androstene- 3,17-dione-3-ethylene ketal (M.P.177.5-178.5 C.; prepared from Sfi-androstaneJ/i-ol-17-one byketalization, bromination of the l6-position with pyridiniumbromideperbromide, oxidation of the OH group in position 3, andketalization to 16-bromo-5fi-androstane-3,17-dione-diethylene-ketal,dehydrobromination with potassium tert-butylate in xylene, and partialketal dissociation with p-toluenesulfonic acid in aqueous acetone).Stirring is continued for minutes, a crude product is precipitated withice water (14.3 g.), and purified by chromatography. 11.7 g.15,16fl-methylene-5fl-androstane-3,17-dione 3 ethylene ketal of meltingpoint 191-193 C. are obtained (from diisopropyl ether).

Example 8 ml. dimethylsulfoxide, 1.44 g. sodium hydride, and 13.25 g.trimethyloxosulfonium iodide are stirred at room temperature until gasdevelopment stops (about 40 minutes). Then, there are added 16.5 g. A-5iz-androstene- 3,17-dione-3-ethylene ketal (M.P. 1485-1495 C.;prepared from A -5-a-androstene-3fi-ol-17-one-17-ethylene ketal (Chem.Listy, 51, 1885 (1957), and JACS 82 (1960) 32-09) by oxidation of the OHgroup in position 3, ketalization of the resulting 3-keto group, andpartial ketal dissociation with p-toluenesulfonic acid in aqueousacetone). The mixture is stirred 90 minutes at room temperature,precipitated with ice water, and the crude product is purified bychromatography. There are obtained 10.7 g.15,1Gfi-methylene-Sa-androstane-3,17-dione 3 ethylene ketal of meltingpoint 157.5-159" C. (from diisopropyl ether).

Example 9 In analogy to Example 1, 17.5 ml. dimethylsulfoxide, 144 mg.sodium hydride, and 1.33 g. trimethyloxosulfonium iodide are stirred 40minutes at room temperature. Then 1.43 g. (5 millimol) A-androstadiene-3B-ol-17- one are added, and stirring is continued forthree hours. The crude product recovered by ice water precipitation ispurified chromatographically, and 15,16,8-methylene-Aandrostene-3/3-ol-17-one is obtained.

Example 10 17.5 g. dimethylsulfoxide, 144 mg. sodium hydride, and 1.33g. trimethyloxosulfonium iodide are stirred at room temperature for 40minutes. Thereafter, 1.42 g. A -androstadiene-3,17-dione (prepared fromA -androstadiene-3B-ol-17-one-17-ethylene ketal by oxidation in position3 and ketal dissociation) are added and stirring continues for 4 hour.The crude product recovered by ice water precipitation is purifiedchromatographically, and 15,16/8-methylene-A -androstene-3,17-dione isobtained.

We claim:

1. Compounds of the formula ii I CH:

wherein is a single or double carbon bond, and the A ring may have thefollowing structures:

Z being hydrogen or methyl; Y being any one of the fol- 15 lowing OK ORO-CH2 .r" y .r" or o-om wherein R is alkyl, and preferably lower alkyl,or acyl,

Z being hydrogen or methyl.

2. 15,l6B-methylene-5a-androstane-3,B-ol-l7-one.

3. 15,16fi-methylene-A -estratriene-3-01-17 one- 3-methyl ether.

4. l5,l6fl-methylene-A -estratriene-3-ol l7 one- 3-tetrahydropyranylether.

5. 15,16/3-methylene-A -estratriene-3-o1-17-one.

6. 15,16B-methyIene-A Q -estratriene-3-ol-17 one- 3-acetate.

7. The method of preparing 15,16fl-rnethylene steroids, of the estraneand androstane series, having the partial formula by methylenatingcorresponding A -17 ketosteroids at the 15,16 double bond by means ofdirnethylmethylenesulfonium oxide, adding diazomethane, then splittingnitrogen from the resultant pyrazoline ring so produced.

References Cited UNITED STATES PATENTS 3,127,396 3/1964 Wiechert et a1.260-2395 3,243,434 3/1966 Krakower 260-239.55 3,338,928 8/1967 Beard eta1 260-397.4 3,365,446 1/1968 Cross et a1 260-23955 ELBERT L. ROBERTS,Primary Examiner U.S. Cl. X.R.

